γ-Aminobutyric acid (GABA), the most abundant inhibitory neurotransmitter, activates both ionotropic GABAA/C and metabotropic GABAB receptors (Hill and Bowery, Nature, 290, 149-152, 1981). GABAB receptors that are present in most regions of the mammalian brain on presynaptic terminals and postsynaptic neurons are involved in the fine-tuning of inhibitory synaptic transmission. Presynaptic GABAB receptors through modulation of high-voltage activated Ca2+ channels (P/Q- and N-type) inhibit the release of many neurotransmitters. Postsynaptic GABAB receptors activates G-protein coupled inwardly rectifying K+ (GIRK) channel and regulates adenylyl cyclase (Billinton et al., Trends Neurosci., 24, 277-282, 2001; Bowery et al., Pharmacol. Rev. 54, 247-264, 2002). Because the GABAB receptors are strategically located to modulate the activity of various neurotransmitter systems, GABAB receptor ligands hence could have potential therapeutic applications in the treatment of anxiety, depression, epilepsy, schizophrenia and cognitive disorders (Vacher and Bettler, Curr. Drug Target, CNS Neurol. Disord. 2, 248-259, 2003; Bettler et al., Physiol Rev. 84, 835-867, 2004).
Native GABAB receptors are heteromeric structures composed of two types of subunits, GABABR1 and GABABR2 subunits (Kaupmann et al., Nature, 386, 239-246, 1997 and Nature, 396, 683-687, 1998). The structure of GABABR1 and R2 show that they belong to a family of G-protein coupled receptors (GPCRs) called family 3. Other members of the family 3 GPCRs include the metabotropic glutamate (mGlu1-8), Calcium-sensing, vomeronasal, pheromone and putative taste receptors (Pin et al., Pharmaco. Ther. 98, 325-354, 2003). The family 3 receptors (including GABAB receptors) are characterized by two distinctly separated topological domains: an exceptionally long extracellular amino-terminal domain (ATD, 500-600 amino acids), which contains a venus flytrap module for the agonist binding (orthosteric site) (Galvez et al., J. Biol. Chem., 275, 41166-41174, 2000) and the 7TM helical segments plus intracellular carboxyl-terminal domain that is involved in receptor activation and G-protein coupling. The mechanism of receptor activation by agonist in GABABR1R2 heterodimer is unique among the GPCRs. In the heteromer, only GABABR1 subunit binds to GABA, while the GABABR2 is responsible for coupling and activation of G-protein (Havlickova et al., Mol. Pharmacol. 62, 343-350, 2002; Kniazeff et al., J. Neurosci., 22, 7352-7361, 2002).
Schuler et al., Neuron, 31, 47-58, 2001 have demonstrated that the GABABR1 knock-out (KO) mice exhibit spontaneous seizures and hyperalgesia. These KO mice have lost all the biochemical and electrophysiological GABAB responses. Interestingly, the GABABR1 KO mice were more anxious in two anxiety paradigm, namely the light-dark box (decreased time in light) and staircase tests (decreased rears and steps climbed). They showed a clear impairment of passive avoidance performance model indicating impaired memory processes. The GABABR1 KO also displayed increased hyperlocomotion and hyperactivity in new environment. The GABABR1 gene is mapped to chromosome 6p21.3, which is within the HLA class I, a region with linkage for schizophrenia, epilepsy and dyslexia (Peters et al., Neurogenetics, 2, 47-54, 1998). Mondabon et al., Am. J. Med. Genet 122B/1, 134, 2003 have reported about a weak association of the Ala20Val polymorphism of GABABR1 gene with schizophrenia. Moreover, Gassmann et al., J Neurosci. 24, 6086-6097, 2004 has shown that GABABR2KO mice suffer from spontaneous seizures, hyperalgesia, hyperlocomotor activity and severe memory impairment, comparable to GABABR1KO mice. Therefore, heteromeric GABABR1R2 receptors are responsible for these phenotypes.
Baclofen (Lioresalθ, β-chlorophenyl GABA), a selective GABAB receptor agonist with EC50=210 nM at native receptor, is the only ligand, which has been used since 1972 in clinical study for the treatment of spasticity and skeletal muscle rigidity in patients following spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, cerebral palsy. Most of the preclinical and clinical studies conducted with baclofen and GABAB receptor agonists were for the treatment of neuropathic pain and craving associated with cocaine and nicotine (Misgeld et al., Prog. Neurobiol. 46, 423-462, 1995; Enna et al., Life Sci, 62, 1525-1530, 1998; McCarson and Enna, Neuropharmacology, 38, 1767-1773, 1999; Brebner et al., Neuropharmacology, 38, 1797-1804, 1999; Paterson et al., Psychopharmacology, 172, 179-186, 2003). In panic disorder patients, Baclofen was shown to be significantly effective in reducing the number of panic attacks and symptoms of anxiety as assessed with the Hamilton anxiety scale, Zung anxiety scale and Katz-R nervousness subscale (Breslow et al., Am. J. Psychiatry, 146, 353-356, 1989). In a study with a small group of veterans with chronic, combat-related posttraumatic stress disorder (PTSD), baclofen was found to be an effective and well-tolerated treatment. It resulted in significant improvements in the overall symptoms of PTSD, most notably the avoidance, emotional numbing and hyperarousal symptoms and also in reduced accompanying anxiety and depression (Drake et al., Ann. Pharmacother. 37, 1177-1181, 2003). In preclinical study, baclofen was able to reverse the reduction in prepulse inhibition (PPI) of the acoustic startle response induced by dizocilpine, but not by apomorphine in rat PPI model of psychosis (Bortolato et al., Psychopharmacology, 171, 322-330, 2004). Therefore, GABAB receptor agonist has a potential in the pharmacological therapy of psychotic disorders. Unfortunately, Baclofen has a number of side-effects including the poor blood-brain-barrier penetration, very short duration of action and narrow therapeutic window (muscle relaxation, sedation and tolerance) that limit its utility.
Urwyler et al., Mol. Pharmacol., 60, 963-971, 2001 have reported on a novel class of GABAB receptor ligands, called positive allosteric modulators, CGP7930 [2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol] and its aldehyde analogue CGP13501. These ligands have no effect on their own at GABAB receptors, but in concert with endogenous GABA, they increase both the potency and maximal efficacy of GABA at the GABABR1R2 (Pin et al., Mol. Pharmacol., 60, 881-884, 2001). Interestingly, recent study with CGP7930 (Binet et al., J Biol Chem., 279, 29085-29091, 2004) has shown that this positive modulator activates directly the seven transmembrane domains (7TMD) of GABABR2 subunit. Mombereau et al., Neuropsychopharmacology, 1-13, 2004 have recently reported on the anxiolytic effects of acute and chronic treatment with the GABAB receptor positive modulator, GS39783 (N,N_-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine) (Urwyler et al., J. Pharmacol. Exp. Ther., 307, 322-330, 2003) in the light-dark box and elevated zero maze test models of anxiety. No tolerance after chronic treatment (21 days) with GS39783 (10 mg/kg, P.O., once daily) was observed. Because the GABAB enhancers have no effect on receptor activity in the absence of GABA, but do enhance allosterically the affinity of the GABAB receptor for the endogenous GABA, it is expected that these ligands should have an improved side effect profile as compared to baclofen. Indeed, GS39783 at 0.1-200 mg/kg, PO had no effect on spontaneous locomotor activity, rotarod, body temperature and traction test in comparison to baclofen, which showed these side effects at 2.5-15 mg/kg, PO. GS39783 did not have any effect on cognition performance as assessed by passive avoidance behavioral test in mice and rats. Furthermore, GS39783 exhibited anxiolytic-like effects in the elevated plus maze (rat), elevated zero maze (mice and rats), and the stress-induced hyperthermia (mice) test paradigms. Therefore, GS39783 represents a novel anxiolytic without side-effects associated with baclofen or benzodiazepines (Cryan et al., J Pharmacol Exp Ther., 310, 952-963, 2004). The preclinical investigation with the CGP7930 and GS39783 has shown that both compounds were effective at decreasing cocaine self-administration in rats (Smith et al., Psychopharmacology, 173, 105-111, 2004). The positive modulator, CGP7930 has also been preclinically studied for the treatment of Gastro-Esophageal Reflux Disease (GERD) and was found to be effective (WO 03/090731, Use of GABAB receptor positive modulators in gastro-intestinal disorders).
Positive allosteric modulators have been reported for other family 3 GPCRs including mGlu1 receptor (Knoflach et al., Proc. Natl. Acad. Sci., USA, 98, 13402-13407, 2001; Wichmann et al., Farmaco, 57, 989-992, 2002), Calcium-sensing receptor (NPS R-467 and NPS R-568) (Hammerland et al., Mol. Pharmacol., 53, 1083-1088, 1998) (U.S. Pat. No. 6,313,146), mGlu2 receptor [LY487379, N-(4-(2-methoxyphenoxy)-phenyl-N-(2,2,2-trifluoroethylsulfonyl)-pyrid-3-ylmethylamine and its analogs] (WO 01/56990, Potentiators of glutamate receptors) and mGlu5 receptor (CPPHA, N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}-2-hydroxybenzamide) (O'Brien et al., J. Pharmaco. Exp. Ther., 27, Jan. 27, 2004). Interestingly, it has been demonstrated that these positive modulators bind to a novel allosteric site located within the 7TMD region, thereby enhancing the agonist affinity by stabilizing the active state of the 7TMD region (Knoflach et al., Proc. Natl. Acad. Sci., USA 98, 13402-13407, 2001; Schaffhauser et al., Mol. Pharmacol., 64, 798-810, 2003). Moreover, the NPS R-467, NPS R-568 (Tecalcet) and related compounds represent the first positive allosteric modulators that entered the clinical trails due to their allosteric mode of action.
WO 2003080580, WO 2005026125 and WO 2005040124 describe quinoline derivatives for the treatment of CNS disorders. Nevertheless, the compounds disclosed in these patent applications are 3-aryl/heteroarylsulfonyl-8-piperazine-quinoline derivatives, which derivatives differ from the compounds of the instant invention.